The objective of this project is the development of an 18F-labeled radiopharmaceutical for PET (positron- emission tomography) imaging myocardial perfusion. Myocardial perfusion imaging (MPI) is the most commonly performed nuclear medicine procedure performed in adults; nearly 60% of all nuclear medicine studies in the U.S. are for the evaluation myocardial perfusion, nearly 10,000,000 studies each year. One reason for the popularity of MPI is its extremely high predictive value for future cardiac events. At the present time, MPI studies are usually carried out using the single-photon radiopharmaceuticals 99mTc-MIBI and 99mTc- tetrofosmin. However, PET imaging offers significant advantages over single-photon imaging for MPI including higher spatial resolution; improved attenuation correction, which is of importance because of the increasing rate of obesity in the US; and the ability to directly measure tracer uptake, which is important in the evaluation of global ischemia. An additional motivation is the current worldwide shortage of 99mTc. The PET MPI tracers currently in use include 82Rb (T1/2=76 s), [13N]NH3 (T1/2=10 min), and [15O]H2O (T1/2=2 min). However, these agents suffer from significant limitations including the high cost of 82Rb and the limited availability of [13N]NH3 and [15O]H2O, which require on-site cyclotrons for production. Fluorine-18 has nearly ideal physical properties for MPI (T1/2=110 min, 97% 2+ yield, low 2+ energy), lower cost than 82Rb, and greater availability than [13N]NH3 and [15O]H2O. There are, however, currently no commercially available 18F-labeled MPI radiopharmaceuticals. Rhodamine dyes are known to accumulate in the heart and therefore offer a promising starting point for the development of an 18F-labeled MPI radiopharmaceutical. The core hypothesis of this proposal is, therefore, that: A PET radiopharmaceutical for the evaluation of myocardial perfusion can be developed based on an 18F- labeled rhodamine dye. This basic premise was recently validated in our laboratory when we observed that 18F-labeled ester derivatives of rhodamine B showed very high accumulation in the heart, minimal accumulation in the liver (which can interfere with visualization of the apex of the left ventricle), and rapid blood clearance. The Specific Aims of the project will expand upon this initial observation and validate this hypothesis. To this end, we will (1) develop a synthesis that produces 18F-labeled rhodamines in high yield, high chemical and radiochemical purity, and high specific activity, (2) evaluate the biological properties of 18F- labeled rhodamines that are important for MPI, and (3) determine which rhodamine dye is optimal for use as an MPI radiopharmaceutical. The successful accomplishment of these Specific Aims will result in the development of a novel and effective radiopharmaceutical for myocardial perfusion imaging with PET that will significantly improve clinical management of patients with cardiac disease.